Cleidocranial dysplasia is an autosomal dominant skeletal disorder resulting from RUNX2 mutations. The influence of RUNX2 mutations on osteoclastogenesis and bone resorption have not been reported. To investigate the role of RUNX2 in osteoclast, RUNX2 expression in macrophages (RAW 264.7 cells) was detected. Stable RAW 264.7 cell lines expressing wild-type RUNX2 or mutated RUNX2 (c.514delT, p.172 fs) were established, and their functions in osteoclasts were investigated. Wild-type RUNX2 promoted osteoclast differentiation, formation of F-actin ring, and bone resorption, while mutant RUNX2 attenuated the positive differentiation effect. Wild-type RUNX2 increased the expression and activity of mTORC2. Subsequently, mTORC2 specifically promoted phosphorylation of AKT at the serine 473 residue. Activated AKT improved the nuclear translocation of NFATc1 and increased the expression of downstream genes, including CTSK. Inhibition of AKT phosphorylation abrogated the osteoclast formation of wild-type macrophages, whereas constitutively activated AKT rescued the osteoclast formation of mutant macrophages. The present study suggested that RUNX2 promotes osteoclastogenesis and bone resorption through the AKT/NFATc1/CTSK axis. Mutant RUNX2 lost the function of regulating osteoclast differentiation and bone remodeling, resulting in the defective formation of the tooth eruption pathway and impaction of permanent teeth in cleidocranial dysplasia. This study, for the first time, verifies the effect of RUNX2 on osteoclast differentiation and bone resorption and provides new insight for the explanation of cleidocranial dysplasia.
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